17-80107705-C-T

Variant names:

• chr17-80107705-C-T
• rs142967546
• NM_000152.5:c.841C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3 PM2_Supporting PM3_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.841C>T variant in GAA is predicted to result in the substitution of arginine by tryptophan at amino acid 281 (p.Arg281Trp). This variant has been reported in four individuals with features consistent with Pompe disease and documented GAA activity (PMID:36299500, clinical diagnostic laboratory - pseudodeficiency variants were ruled out) and another individual with features consistent with infantile onset Pompe disease on enzyme replacement therapy but GAA activity not provided (PMID:31086307). In addition, the variant was reported in an infant identified on newborn screen (PMID:33202836), as well as in five individuals reported to have later-onset disease (PMID:22081099, 33073009) (PP4_Moderate). Four patients are reported to be compound heterozygous for the variant and a pathogenic variant in GAA, including c.172C>T (p.Gln58Ter) (PMID:36299500, phase unknown) (ClinVar Variation ID: 188903; SCV001371756.1), c.2481+102_2646+31del (clinical diagnostic laboratory; phase unknown) (ClinVar Variation ID: 657307), c.2161delG (clinical diagnostic laboratory; confirmed in trans) (ClinVar Variation ID: 932900, SCV001371755.1), and c.-32-13T>G (PMID:33202836; phase unknown) (ClinVar Variation ID: 4027) (PM3_Strong). The score for the in silico meta-predictor REVEL, 0.786, suggests that the variant is deleterious, meeting PP3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (European non-Finnish), meeting PM2_Supporting. To our knowledge, the results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 283894). This variant meets the criteria to the classified as likely pathogenic for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2019. Since then, the data for this variant have been re-evaluated - no new data were identified. The classification of likely pathogenic was reapproved on April 8, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815025/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00054 (1 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:13 U:5 O:1
• Conservation: PhyloP100: 2.23
• Publications: 14 publications found

Genes affected

GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

GAA Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.841C>T	p.Arg281Trp	missense	Exon 4 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.841C>T	p.Arg281Trp	missense	Exon 5 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.841C>T	p.Arg281Trp	missense	Exon 4 of 20	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.841C>T	p.Arg281Trp	missense	Exon 4 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.841C>T	p.Arg281Trp	missense	Exon 5 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.841C>T	p.Arg281Trp	missense	Exon 4 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.000313 AC: 47 AN: 150096 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000981

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000623

Gnomad OTH AF: 0.000490

GnomAD2 exomes AF: 0.000206 AC: 51 AN: 247128 AF XY: 0.000194

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000415

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000544 AC: 794 AN: 1460482 Hom.: 1 Cov.: 33 AF XY: 0.000546 AC XY: 397 AN XY: 726584

African (AFR) AF: 0.0000598 AC: 2 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000664 AC: 738 AN: 1111790

Other (OTH) AF: 0.000878 AC: 53 AN: 60346

GnomAD4 genome AF: 0.000306 AC: 46 AN: 150216 Hom.: 0 Cov.: 34 AF XY: 0.000287 AC XY: 21 AN XY: 73270

African (AFR) AF: 0.0000978 AC: 4 AN: 40892

American (AMR) AF: 0.00 AC: 0 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.00 AC: 0 AN: 4732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000608 AC: 41 AN: 67428

Other (OTH) AF: 0.000484 AC: 1 AN: 2064

Alfa AF: 0.000396 Hom.: 0

Bravo AF: 0.000317

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	2	-	Glycogen storage disease, type II (10)
4	3	-	not provided (7)
1	-	-	Cardiovascular phenotype (1)
1	-	-	GAA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		2.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MVP		1.0
MPC		0.55
ClinPred		0.98	D
GERP RS		2.8
Varity_R		0.94
gMVP		0.95
Mutation Taster		=63/37	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142967546; hg19: chr17-78081504; COSMIC: COSV56409042; COSMIC: COSV56409042;